AUTHOR=Rajamani Bharathi M. , Illangeswaran Raveen Stephen Stallon , Benjamin Esther Sathya Bama , Balakrishnan Balaji , Jebanesan Daniel Zechariah Paul , Das Saswati , Pai Aswin Anand , Vidhyadharan Rakhi Thalayattu , Mohan Ajith , Karathedath Sreeja , Abraham Aby , Mathews Vikram , Velayudhan Shaji R. , Balasubramanian Poonkuzhali 

TITLE=Modulating retinoid-X-receptor alpha (RXRA) expression sensitizes chronic myeloid leukemia cells to imatinib in vitro and reduces disease burden in vivo

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1187066

DOI=10.3389/fphar.2023.1187066

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> The ligand-activated transcription factors, nuclear hormone receptors (NHRs), remain unexplored in hematological malignancies except for retinoic acid receptor alpha (<italic>RARA</italic>).</p><p><bold>Methods:</bold> Here we profiled the expression of various NHRs and their coregulators in Chronic myeloid leukemia (CML) cell lines and identified a significant differential expression pattern between inherently imatinib mesylate (IM)-sensitive and resistant cell lines.</p><p><bold>Results:</bold> Retinoid-X-receptor alpha (<italic>RXRA</italic>) was downregulated in CML cell lines inherently resistant to IM and in primary CML CD34<sup>+</sup> cells. Pre-treatment with clinically relevant RXRA ligands improved sensitivity to IM <italic>in-vitro</italic> in both CML cell lines and primary CML cells. This combination effectively reduced the viability and colony-forming capacity of CML CD34<sup>+</sup> cells <italic>in-vitro. In-vivo,</italic> this combination reduced leukemic burden and prolonged survival. Overexpression (OE) of <italic>RXRA</italic> inhibited proliferation and improved sensitivity to IM <italic>in-vitro</italic>. <italic>In-vivo, RXRA</italic> OE cells showed reduced engraftment of cells in the bone marrow, improved sensitivity to IM, and prolonged survival. Both <italic>RXRA OE</italic> and ligand treatment markedly reduced BCR::ABL1 downstream kinase activation, activating apoptotic cascades and improving sensitivity to IM. Importantly, RXRA OE also led to the disruption of the oxidative capacity of these cells.</p><p><bold>Conclusion:</bold> Combining IM with clinically available RXRA ligands could form an alternative treatment strategy in CML patients with suboptimal response to IM.</p>